Mutational screening of Greek patients with axonal Charcot‐Marie‐Tooth disease using targeted next‐generation sequencing: Clinical and molecular spectrum delineation

Abstract

Background and aimsAxonal forms of Charcot–Marie–Tooth disease (CMT) are classified as CMT2, distal hereditary motor neuropathy (dHMN) or hereditary sensory neuropathy (HSN) and can be caused by mutations in over 100 genes. We presently aimed to investigate for the first time the genetic landscape of axonal CMT in the Greek population.MethodsSixty index patients with CMT2, dHMN or HSN were screened by a combination of Sanger sequencing (GJB1) and an NGS custom‐made gene panel covering 24 commonly mutated genes in axonal CMT.ResultsOverall, 20 variants classified as pathogenic or likely pathogenic were identified in heterozygous state in 20 index cases, representing 33.3% of the cohort. Of these, 14 were known pathogenic/ likely pathogenic and 6 were designated as such according to ACMG classification, after in silico evaluation, testing for familial segregation and further literature review. The most frequently involved genes were GJB1 (11.7%), MPZ (5%) and MFN2 (5%), followed by DNM2 (3.3%) and LRSAM1 (3.3%). Single cases were identified with mutations in BSCL2, HSPB1 and GDAP1.InterpretationA wide phenotypic variability in terms of severity and age of onset was noted. Given the limited number of genes tested, the diagnostic yield of the present panel compares favorably with studies in other European populations. Our study delineates the genetic and phenotypic variability of inherited axonal neuropathies in the Greek population and contributes to the pathogenicity characterization of further variants linked to axonal neuropathies.This article is protected by copyright. All rights reserved.

Investigating Mutations of 288 Genes in a Family with Charcot-Marie-Tooth Disease by the Whole-Exome Sequencing Method in Khuzestan Province

“…The most common genes involved included GJB1 (11.7%), MPZ (5%), and MFN2 (5%), followed by DNM2 (3.3%) and LRSAM1 (3.3%). Single cases with mutations in BSCL2, HSPB1, and GDAP1 were also identified (16). The research implies that the use of new techniques will notably advance the understanding of genes and mutations associated with this disease while also impacting the cost of diagnosis.…”